Studies were conducted under the following NationalClinicalTrials protocols: NCT02743377, NCT03632226, NCT03912428, NCT03324646, and NCT03861000. Examples of progress made during the prior year are summarized below. 1) The newly developed PET radioligand 11CPS13 is capable of imaging cyclooxygenase-1 (COX-1) in healthy human subjects. NCT03324646 For several years, we have focused on developing much-needed effective, sensitive, and reliable radioligands capable of imaging neuroinflammation. Our recent efforts have focused on the cyclooxygenase (COX) system, which is implicated in the pathophysiology of brain diseases. The COX system comprises two isoforms, COX-1 and COX-2, which are key enzymes in neuroinflammation. Past studies from our laboratory found that our newly developed radioligand, 11CPS13, was selective for COX-1 and, furthermore, could be used to establish the in vivo distribution of COX-1 in brain and peripheral organs. Expanding on this work, a recent study from our laboratory assessed whether 11CPS13, which has shown excellent in vivo selectivity in previous animal studies, could be used to quantify constitutive levels of COX-1 in healthy human brain. Towards this end, brain test-retest scans with concurrent arterial blood samples were obtained in 10 healthy subjects. One- and two-tissue compartment models, as well as Logan graphical analysis were compared, and test-retest reliability and time stability of total distribution volume (VT) were assessed. Correlation analyses were conducted between brain regional VT and COX-1 transcript levels provided in the Allen Human Brain Atlas. In addition, the utility of an alternative simplified method of quantifying 11CPS13 binding was evaluated. We found that, in brain, 11CPS13 showed the highest uptake in the hippocampus and occipital cortex. The pericentral cortex also showed relatively higher uptake compared to adjacent neocortices. The two-tissue compartment model showed the best fit in most brain regions, although the Logan graphical analysis also showed reasonably good fit. VT values estimated with the two-tissue compartment model showed excellent test-retest variability (range: 6.0 8.5%) and good reliability (intraclass correlation coefficient range: 0.74 0.87). VT values also showed excellent time stability in all brain regions, confirming that there was no radiometabolite accumulation and that shorter scans were still able to reliably measure VT. Significant correlation was observed between VT and COX-1 transcript levels (r = 0.82, P = 0.007), indicating that 11CPS13 binding reflects actual COX-1 density in human brain. The alternative simplified method, which used fewer blood data at 10-90 minutes, showed good consistency with VT, although the value was overestimated by 4.2% in whole brain. Notably, our results are the first-in-human evaluation of the ability of 11CPS13 to image COX-1 in brain. As described in other annual reports, we have also developed 11CMC1, a radioligand selective for COX-2; 11CPS13 and 11CMC1 are the first radioligands for COX-1 and COX-2, respectively, that act directly at these targets. The present results are currently being prepared for publication. If our ongoing studies continue to suggest that these two new radioligands can localize and quantify COX-1 and COX-2 in humans, we will apply them to disorders known or likely to be associated with neuroinflammation, including dementias and MDD. Such studies in neuropsychiatric disorders have three potential uses: exploring pathophysiology, measuring in vivo selectivity for the isozymes, and guiding therapeutic trials. The present results indicate that such studies with 11CPS13 are warranted. 2) Subjects with McCune-Albright Syndrome (MAS) show greater binding of rolipram than healthy controls in areas known to be affected by the disorder; rolipram is a reversible inhibitor of phosphodiesterase 4 (PDE4) that can be used to image cyclic adenosine monophosphate (cAMP) signaling. NCT02743377 McCune-Albright syndrome (MAS) is a rare mosaic disorder arising from mutations of the GNAS gene, which encodes the 3, 5-cyclic adenosine monophosphate (cAMP) pathway-associated G-protein, Gs. This mutation results in dysregulation of the cAMP signaling cascade, leading to upregulation of phosphodiesterase type 4 (PDE4), an enzyme that catalyzes the hydrolysis of cAMP. In past studies from our laboratory, positron emission tomography (PET) imaging of PDE4 using 11C(R)-rolipram was successfully used to study the in vivo activity of the cAMP cascade. Rolipram is a reversible inhibitor of PDE4, and binding of 11C(R)-rolipram provides a measure of the activity of this enzyme in brain. Due to a feedback mechanism, in vivo binding of 11C(R)-rolipram reflects the activity of the cAMP cascade; essentially, increased cAMP stimulates protein kinase A (PKA), which phosphorylates PDE4 that, in turn, increases rolipram binding. Clinical manifestations of MAS in a given individual (for instance, fibrous dysplasia) are determined by the timing of the GNAS mutation during embryogenesis, the tissues involved, and the role of Gs in the affected tissues. While animal models of fibrous dysplasia have shown increased PDE4 activity, this correlation has not been shown in humans with fibrous dysplasia. Therefore, it is unknown whether fibrous dysplasia, as well as other symptoms of MAS, are related to increased PDE4 activity in humans. The present study performed 11C-(R)-rolipram whole body and brain PET scans in MAS patients as well as healthy controls in order to evaluate whether subjects with MAS show greater rolipram binding than healthy controls in areas known to affected by the disorder. We found that 11C-(R)-rolipram binding in the body correlated with known locations of fibrous dysplasia in patients with MAS; in contrast, no uptake was observed in the bones of healthy controls. 11C-(R)-rolipram uptake in peripheral organs was not statistically significant between groups. No evidence of mosaicism was observed throughout the brain regions examined. These results are consistent with animal studies showing that increased cAMP leads to PKA activation, which in turn increases PDE4 phosphorylation. This study revealed that rolipram binding does reflect increased cAMP pathway activation. These results are currently being prepared for publication. In future studies, we will seek to determine whether the increased binding is specific by performing whole-body blocking scans with the PDE4 inhibitor roflumilast.